Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective:To observe the efficacy and safety of Tofacitinib in treating elderly rheumatoid arthritis(RA), in order to provide clinical evidence.Methods:In the randomized control trial, a total of 90 elderly RA patients admitted to the Department of Rheumatology of the First Affiliated Hospital of Soochow University from January 2019 to January 2021 were selected and divided into Methotrexate group(MTX group, MTX 10mg, qw, n=45)and Tofacitinib group(TOF group, oral 5mg, bid, n=45). The efficacy and safety of the two groups were evaluated at week 12.The primary endpoint was the proportion of patients meeting the American College of Rheumatology 50%(ACR50)improvement response criteria at week 12.Secondary endpoints included ACR20/70 improvement response, proportion of patients who met treat-to-target(T2T)criteria, including Disease Activity Score in 28 joints using erythrocyte sedimentation rate(DAS28-ESR), Disease Activity Score in 28 joints using C-reactive protein level(DAS28-CRP), clinical disease activity index(CDAI), and simplified disease activity index(SDAI), and patient-reported outcomes(PROs)which included changes compared to baseline in pain visual analog scale(VAS)and Health Assessment Questionnaire Disability Index(HAQ-DI)score, at week 12.Safety outcomes including drug-related adverse events, serious adverse events, dropping out due to adverse events, and deaths were assessed throughout.Results:Five patients in each group withdrew from the trial due to adverse events, and the number of patients who finally completed the observation was 40 in each group.At week 12, the ACR50 response rate was higher in TOF group than in MTX group[35%(14/40) vs.12.5%(5/40), χ2=5.591, P=0.018)], achieving the primary endpoint.When comparing TOF vs.MTX group, the ACR20 response rate[55%(22/40) vs.25%(10/40), χ2=7.500, P=0.006]and ACR70 response rate[25%(10/40) vs.7.5%(3/40), χ2=4.501, P=0.034], and proportions of indexes of disease remission including DAS28-ESR<2.6[25%(11/40) vs.7.5%(3/40), χ2=4.501, P=0.034], or DAS28-CRP<2.6[27.5%(11/40) vs.7.5%(3/40), χ2=5.541, P=0.019], or CDAI≤2.8[30%(12/40) vs.10%(4/40), χ2=5.000, P=0.025], or SDAI≤3.3[27.5%(11/40) vs.7.5%(3/40), χ2=5.541, P=0.019], and the proportions of patients with low disease activity including DAS28-ESR≤3.2[32.5%(14/40) vs.12.5%(5/40), χ2=5.591, P=0.018], or DAS28-CRP≤3.2[32.5%(14/40) vs.12.5%(5/40), χ2=5.591, P=0.018], or CDAI≤10[37.5%(15/40) vs.17.5%(7/40), χ2=4.013, P=0.045], or SDAI≤11[37.5%(15/40) vs.15%(6/40), χ2=5.230, P=0.022], as well as changes compared to baseline data in pain VAS[(26.51±8.32)scores vs.(14.16±4.39)scores, t=8.371, P<0.001]and in HAQ-DI score(0.65±0.24 vs.0.32±0.06, t=9.387, P<0.001)were all better in the TOF group than in the MTX group at week 12.During the 12-week observation period, the number of patients with infection and hyperlipidemia was higher in TOF group than in MTX group, while the number of patients with abnormal blood cell count and liver function was lower than that in MTX group, but the differences were not statistically significant(all P<0.05). Conclusions:Tofacitinib has good efficacy and safety in the elderly RA.In patients over 70 years of age who are at high risk of infection, tofacitinib should be used with caution.

Cardiomyopathy, Dilated/metabolism* ; Humans ; Microfilament Proteins/metabolism* ; Models, Cardiovascular ; Mutation ; Myocytes, Cardiac ; Pluripotent Stem Cells/metabolism* ; Transcription Factors/metabolism* ; Troponin T/metabolism*

To develop an intelligent lower limb rehabilitation instrument which could realize the quantification and visualization of lower limbs' raising angle and frequency, using the smart client to realize the remote control, autonomous data acquisition and the establishment of database. Doctors had the access to the database in order to adjust the rehabilitation program in time to meet the individual requirement. We realized the design of intelligent lower limb instrument based on the Andriod smartphone, which is suitable for clinical and family use.
Computers ; Databases, Factual ; Humans ; Leg ; Mobile Applications ; Rehabilitation ; instrumentation ; Smartphone

Objective To investigate the expression of serum B factor in the peripheral blood of patients with systemic lupus erythematosus (SLE),and explore its role in the pathogenesis.Methods Seventy eight patients with SLE in our hospital and 46 healthy persons were eligible to participate in this study.Rate nphelometyr was used to test serum B factor for 78 patients with SLE and 46 healthy controls.According to systemic lupus erythematosus disease activity index (SLEDAI),participants were divided into steady SLE group (SLEDAI ＜ 5) and active SLE group (SLEDAI ≥5),which was further divided into mild,moderate,and serious subgroups.The differences in serum B factor between SLE patients and healthy controls,including SLE patients with different severity,were all compared.Then we analyzed the differences in serum B factor and other laboratory and clinical indexes between active and steady SLE patients.The correction of serum B factor and other laboratory and clinical indexes were also analyzed.Results Compared to healthy controls,patients with SLE had significantly lower value of serum B factor [(27.13 ± 8.98) mg/dl vs (36.73 ± 5.47) mg/dl,t =7.4,P ＜ 0.01].Compared to steady SLE group,SLE active group had significantly lower level of serum factor B,C3 and C4,and also had significant higher level of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (all P ＜ 0.05).Moreover,There were significant differences in the lower level of serum B factor between subgroups.Correlation analysis showed that the level of serum B factor was negatively associated with the levels of CRP and SLEDAI scores,whereas serum B factor was positively associated with the levels of C3 and C4 (all P ＜ 0.05).Conclusions Serum B factor is related to SLE.Serum B factor might be involved in the pathogenesis of SLE.Detection of serum B factor is helpful for diagnosis and evaluation of SLE disease activity.

Objective To investigate the initial manifestation and disease onset feature of systemic lupus erythematosus(SLE) in the past ten years in fifteen hospitals in Jiangsu Province.Methods Data was collected by the same Methodsin all the participated hospitals and then it was summarized for retrospective analysis.Two groups were compared by chi-square test.Results ① One thousand nine hundred and fifty eight patients were investigated and the male-to-female ratio was 1∶15.0.② One thousand seven hundred and ninty eight patients had clear initial manifestations.The most common initial manifestations were skin and mucosal lesions(769 cases,42.8％ ) and arthritis (697 cases,38.8％ ).The main skin lesion was malar rash (706 cases).Arthritis was found to be more common in female than male.③ All hospitalized patients at their first admission showed multiple organ/system involvement:the most common involvement was skin and mucous membrane (82.3％),hematologic damage (74.0％),in which at least one series of blood cells were involved,arthritis (1156 cases,56.5％ ) much more than myositis (51 cases),proteinuria 1046 cases and hematuria in 385 cases.Renal biopsy pathology showed type Ⅳ glomerulonephritis.Conclusion ① SLE patients are mainly female and the male to female ratio is 1∶15.0.② The most common initial manifestations are skin and mucosal lesions.③ The most commonly involved organ/system are skin and mucous membrane,blood,joint and kidney.The most common pathological changes shown in renal biopsy is type Ⅳ glomerulonephritis.